Filed on behalf of Celgene Corporation
`
`By: Heather M. Petruzzi
`Laura Macro, Ph.D.,
`Gabriel J. Rosanio, Ph.D.
`Wilmer Cutler Pickering Hale and Dorr LLP
`2100 Pennsylvania Avenue N.W.
`Washington, DC 20037
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC.
`Petitioner
`
`v.
`
`CELGENE CORPORATION
`Patent Owner of
`U.S. Patent No. 8,846,628 B2 to Etter et al.
`
`
`IPR Trial No. IPR2023-00512
`
`
`PATENT OWNER’S OBJECTIONS TO EVIDENCE
`UNDER 37 C.F.R. § 42.64
`
`
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`
`
`
`By: Heather M. Petruzzi
`Laura Macro, Ph.D.,
`Gabriel J. Rosanio, Ph.D.
`Wilmer Cutler Pickering Hale and Dorr LLP
`2100 Pennsylvania Avenue N.W.
`Washington, DC 20037
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC.
`Petitioner
`
`v.
`
`CELGENE CORPORATION
`Patent Owner of
`U.S. Patent No. 8,846,628 B2 to Etter et al.
`
`
`IPR Trial No. IPR2023-00512
`
`
`PATENT OWNER’S OBJECTIONS TO EVIDENCE
`UNDER 37 C.F.R. § 42.64
`
`
`
`
`
`
`
`
`
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`Pursuant to 37 C.F.R. § 42.64, Patent Owner hereby objects under the
`
`Federal Rules of Evidence (“FRE”) and 37 C.F.R. § 42.62 to the admissibility of
`
`evidence that Petitioner filed in support of its Petition. Patent Owner’s objections
`
`apply equally to Petitioner’s reliance on these exhibits in any subsequently filed
`
`documents. These objections are timely, having been filed within ten business days
`
`of the Institution Decision (July 20, 2023).
`
`Exhibits 1002
`
`Patent Owner objects to Exhibits 1002, the Declaration of Dr. Buckton.
`
`Patent Owner objects to ¶¶ 39, 48, 50, 66, 79, 93, 104, 112, 119, 121, 122, 125,
`
`126, 136-138, 140, 143, 144, 149, 152-154, 156, 157, 163, 166-168, 171, 173-175,
`
`178, 179, 181, 182, 184, and 187 of Exhibit 1002, and all paragraphs that rely on
`
`those paragraphs. These paragraphs lack a disclosed basis of sufficient facts or data
`
`(FRE 705; 37 C.F.R. § 42.65), are not based on sufficient facts or data, and/or are
`
`not the product of reliable principles and methods (FRE 702). Additionally, Patent
`
`Owner objects to the above referenced paragraphs of Exhibit 1002, and all
`
`paragraphs that rely on those paragraphs as misleading, incomplete, and lacking
`
`relevance and because any probative value is substantially outweighed by the
`
`danger of unfair prejudice, confusing the issues, misleading the fact finder, undue
`
`delay, wasting time, and needlessly presenting cumulative evidence (FRE 106,
`
`
`
`– 1 –
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`401, 402, and 403). In particular, Patent Owner objects to:
`
` ¶¶ 39, 48, 50, 66, 79, 93, 104, 112, 119, 121, 122, 125, 126, 136-138,
`
`140, 143, 144, 149, 152-154, 156, 157, 163, 166-168, 171, 173-175,
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`178, 179, 181, 182, 184, and 187 as misleading, incomplete, and
`
`irrelevant because they lack support for the contentions for which they
`
`are cited;
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` ¶¶ 40-42 as misleading, incomplete, and irrelevant because they lack
`
`support for the contentions for which they are cited and improperly
`
`characterize the teachings of Atadja (Exhibit 1005);
`
` ¶ 49 as misleading, incomplete, and irrelevant because it lacks support
`
`for the contentions for which it is cited and improperly characterize
`
`the teachings of Gibson (Exhibit 1006).
`
`Additionally, Patent Owner further objects to ¶¶ 1-42, 44-91, 93-107, 113-
`
`118, 123-125, 129-137, 139, 144-151, 154, 155, 157-166, 168-171, 177-186, and
`
`191-193 of Exhibit 1002, and all paragraphs that rely on those paragraphs. These
`
`paragraphs are irrelevant (FRE 401 and 402), and any probative value is
`
`substantially outweighed by the risk of undue prejudice and/or confusion (FRE
`
`403). These paragraphs are not directly cited in the Petition and the relevance of
`
`
`
`– 2 –
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`these paragraphs is not apparent (FRE 401, 402 and 403).
`
`Patent Owner further objects to ¶¶ 35, 43, 51, 55, 61, 69, and 163 which
`
`contain citations to Exhibits that are not cited in the Petition and/or that form no
`
`part of the grounds on which inter partes review was instituted, as irrelevant (FRE
`
`401 and 402).
`
`Exhibits 1003
`
`Patent Owner objects to Exhibit 1003, the Declaration of Dr. Batchelor.
`
`Patent Owner objects to ¶¶ 19, 20, 22, 25, 27, 28, 30, 32, 34, 35, and 43 of Exhibit
`
`1003, and all paragraphs that rely on those paragraphs. These paragraphs lack a
`
`disclosed basis of sufficient facts or data (FRE 705; 37 C.F.R. § 42.65). Further,
`
`the above paragraphs proport to be related to “[i]n silico modeling of PK
`
`properties” (Exhibit 1003 at ¶ 19) but fail to provide sufficient description of the
`
`program used for this modeling. For at least this reason, Patent Owner also objects
`
`to the above paragraphs, and all paragraphs that rely on those paragraphs, on the
`
`basis that they are not based on sufficient facts or data, not the product of reliable
`
`principles and methods, and/or not a reliable application of the principles and
`
`methods to the facts (FRE 702 and 703). Additionally, Patent Owner objects to the
`
`above referenced paragraphs of Exhibit 1003, and all paragraphs that rely on those
`
`paragraphs, as lacking relevance, incomplete, and because any probative value is
`
`substantially outweighed by the danger of unfair prejudice, confusing the issues,
`
`
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`– 3 –
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`misleading the fact finder, undue delay, wasting time, and/or needlessly presenting
`
`cumulative evidence because they lack support for the contentions for which they
`
`are cited (FRE 106, 401, 402, and 403).
`
`Additionally, Patent Owner objects to ¶¶ 1-19, 21, 22, 24, 27, 28, and 48 as
`
`well as appendices III.A, III.A.1, III.B, III.C, III.D, and III.E of Exhibit 1003, and
`
`all paragraphs that rely on those paragraphs and appendices, as lacking relevance,
`
`incomplete, and because any probative value is substantially outweighed by the
`
`danger of unfair prejudice, confusing the issues, misleading the fact finder, undue
`
`delay, wasting time, and/or needlessly presenting cumulative evidence (FRE 106,
`
`401, 402, and 403). These paragraphs are not directly cited in the Petition and the
`
`relevance of these paragraphs is not apparent (FRE 401 and 402).
`
`Further, Patent Owner objects to ¶¶ 19-47 as well as Appendices I-III
`
`including Appendices I.A.1, I.A.2, I.B, I.C, I.D.1, I.D.2, I.D.3, I.D.4, I.D.5, II.A,
`
`II.A.1, II.B, II.C, II.D, II.E, III.A, III.A.1, III.B, III.C, III.D, and III.E under 37
`
`C.F.R. § 42.65. To the extent these paragraphs and appendices are, or contain,
`
`technical test or data from such a test, they lack support and explanation in a
`
`sufficient affidavit (37 C.F.R. § 42.65).
`
`Patent Owner further objects to ¶¶ 18, 22, 27, 34, 35, 38, 41, and 45 which
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`contain citations to Exhibits that are not cited in the Petition and/or that form no
`
`part of the grounds on which inter partes review was instituted, as irrelevant (FRE
`
`
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`– 4 –
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
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`401 and 402).
`
`Exhibit 1006
`
`Patent Owner objects to Exhibit 1006, what purports to be a copy of Gibson,
`
`M., Ch. 11, Oral Solid Dosage Forms, PHARMA. PREFORMULATION AND
`
`FORMULATION, CRC Press (2001). Patent Owners object to this Exhibit as not
`
`properly authenticated under FRE 901 because Petitioner has not presented
`
`sufficient evidence that the document is authentic nor that the document is self-
`
`authenticating under FRE 902. Patent Owners further object on the basis that this is
`
`not an original document under FRE 1002, an authentic duplicate under FRE 1003,
`
`nor a document that falls under any exceptions to the original-document
`
`requirement, including those of FRE 1004. Petitioner has not established that
`
`Gibson is a “printed publication” under 35 U.S.C. §102(b) that was published in
`
`2001 at least because the Exhibit bears no library stamp corresponding to that date,
`
`nothing in the Exhibit associates the Gibson chapter to the specific version of the
`
`textbook, and inconsistent page sizing within the Exhibit suggests that it is a
`
`compilation of multiple documents pieced together by Petitioner.
`
`To the extent Exhibit 1006 is being offered to prove the truth of the matter
`
`asserted, Patent Owner also objects to the exhibit as constituting inadmissible
`
`
`
`– 5 –
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`hearsay under FRE 801 and 802 that does not fall under any exceptions, including
`
`those of FRE 803, 804, 805, or 807.
`
`Patent Owner further objects to any paragraph of exhibits 1002 and 1003 to
`
`the extent they rely on Exhibit 1006 for at least the reasons identified here.
`
`Exhibit 1048
`
`Patent Owner objects to Exhibit 1048 as lacking relevance, incomplete, and
`
`because any probative value is substantially outweighed by the danger of unfair
`
`prejudice, confusing the issues, misleading the fact finder, undue delay, wasting
`
`time, and/or needlessly presenting cumulative evidence (FRE 106, 401, 402, and
`
`403). Patent Owner further objects to this exhibit under FRE 401, 402, and 403
`
`because the exhibit is not cited in the Petition, or in paragraphs of the Buckton
`
`Declaration, or the Batchelor Declaration relied upon in the Petition.
`
`Patent Owner further objects to this document as not properly authenticated
`
`under FRE 901 because Petitioner has not presented sufficient evidence that the
`
`document is authentic nor that the document is self-authenticating under FRE 902.
`
`Patent Owner further objects on the basis that this is not an original document
`
`under FRE 1002, an authentic duplicate under FRE 1003, nor a document that falls
`
`under any exceptions to the original-document requirement, including those of
`
`FRE 1004.
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`
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`– 6 –
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`To the extent exhibit 1048 is being offered to prove the truth of the matter
`
`asserted, Patent Owner also objects to the exhibit as constituting inadmissible
`
`hearsay under FRE 801 and 802 that does not fall under any exceptions, including
`
`those of FRE 803, 804, 805, or 807.
`
`Patent Owner further objects to any paragraph of exhibits 1002 and 1003 to
`
`the extent they rely on Exhibit 1048 for at least the reasons identified here.
`
`Exhibits 1020, 1049, and 1050
`
`Patent Owner objects to Exhibits 1020, 1049, and 1050 as lacking relevance,
`
`incomplete, and because any probative value is substantially outweighed by the
`
`danger of unfair prejudice, confusing the issues, misleading the fact finder, undue
`
`delay, wasting time, and/or needlessly presenting cumulative evidence (FRE 106,
`
`401, 402, and 403). Patent Owner further objects to these exhibits under FRE 401,
`
`402, and 403 because the exhibits are not cited in the Petition, or in paragraphs of
`
`the Buckton Declaration, or the Batchelor Declaration relied upon in the Petition.
`
`To the extent exhibits 1020, 1049, and 1050 are being offered to prove the
`
`truth of the matter asserted, Patent Owner also objects to the exhibits as
`
`constituting inadmissible hearsay under FRE 801 and 802 that does not fall under
`
`any exceptions, including those of FRE 803, 804, 805, or 807.
`
`Patent Owner further objects to any paragraph of exhibits 1002 and 1003 to
`
`the extent they rely on exhibits 1020, 1049, and 1050 for at least the reasons
`
`
`
`– 7 –
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`
`identified here.
`
`Exhibits 1013, 1027, 1029, 1030, and 1032
`
`Patent Owner objects to Exhibits 1013, 1027, 1029, 1030, and 1032. Patent
`
`Owner objects to these documents as not properly authenticated under FRE 901
`
`because Petitioner has not presented sufficient evidence that the documents are
`
`authentic nor that the documents are self-authenticating under FRE 902. Patent
`
`Owner further objects on the basis that these are not original documents under FRE
`
`1002, authentic duplicates under FRE 1003, nor documents that falls under any
`
`exceptions to the original-document requirement, including those of FRE 1004.
`
`To the extent exhibits 1013, 1027, 1029, 1030, and 1032 are being offered to
`
`prove the truth of the matter asserted, Patent Owner also objects to the exhibits as
`
`constituting inadmissible hearsay under FRE 801 and 802 that does not fall under
`
`any exceptions, including those of FRE 803, 804, 805, or 807.
`
`Patent Owner further objects to any paragraph of exhibits 1002 and 1003 to
`
`the extent they rely on exhibits 1013, 1027, 1029, 1030, and 1032 for at least the
`
`reasons identified here.
`
`Exhibits 1012, 1034 and 1041
`
`Patent Owner objects to Exhibits 1012, 1034, and 1041. Patent Owner
`
`objects to these documents as not properly authenticated under FRE 901 because
`
`Petitioner has not presented sufficient evidence that the documents are authentic
`
`
`
`– 8 –
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`nor that the documents are self-authenticating under FRE 902. Patent Owner
`
`further objects on the basis that these are not original documents under FRE 1002,
`
`authentic duplicates under FRE 1003, nor documents that falls under any
`
`exceptions to the original-document requirement, including those of FRE 1004.
`
`To the extent exhibits 1012, 1034, and 1041 are being offered to prove the
`
`truth of the matter asserted, Patent Owner also objects to the exhibits as
`
`constituting inadmissible hearsay under FRE 801 and 802 that does not fall under
`
`any exceptions, including those of FRE 803, 804, 805, or 807.
`
`Patent Owner further objects to any paragraph of exhibits 1002 and 1003 to
`
`the extent they rely on exhibits 1012, 1034, and 1041 for at least the reasons
`
`identified here.
`
`Exhibits 1052, 1053, 1054, 1055, 1056, 1057, 1058, and 1059
`
`Patent Owner objects to Exhibits 1052, 1053, 1054, 1055, 1056, 1057, 1058,
`
`and 1059. Exhibits 1052, 1053, and 1054 purport to be “The SDF file for the
`
`PubChem compound entry for Azacitidine (PubChem CID 9444) (September 16,
`
`2004) (‘Conformer3D_CID_9444 (1).sdf’), printed to PDF,” “ADMET Predictor
`
`Output file (‘Azacitidine ADMET.txt’), printed to PDF,” and “CDD file for 200
`
`mg dose (‘Azacitidine 200 mg.cdd’), printed to PDF,” respectively, used for “[i]n
`
`silico modeling of PK properties” (Exhibit 1003 at ¶ 19; see also id. at ¶¶ 33, 42,
`
`fn. 3). 1053, 1054, 1055, 1056, 1057, 1058, and 1059 purport to be “ADMET
`
`
`
`– 9 –
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`Predictor Output file (‘Azacitidine ADMET.txt’), printed to PDF,” “CDD file for
`
`200 mg dose (‘Azacitidine 200 mg.cdd’), printed to PDF,” “IV plasma
`
`concentration-time data file for 200 mg dose (‘Azacitidine 200 mg.ipd’), printed to
`
`PDF,” “Result data file for 200 mg dose (‘Azacitidine 200 mg All Data.txt’),
`
`printed to PDF,” “CDD file for 400 mg dose (‘Azacitidine 400 mg.cdd’), printed to
`
`PDF,” “IV plasma concentration-time data file for 400 mg dose (‘Azacitidine 400
`
`mg.ipd’), printed to PDF,” “Result data file for 400 mg dose (‘Azacitidine 400 mg
`
`All Data.txt’), printed to PDF,” respectively, generated by the in silico modeling
`
`(see Exhibit 1003 at ¶¶ 36, 38, 42, 47). These documents contain columns of data
`
`without explanation of their meanings, how they were used in the purported in
`
`silico modeling of PK properties, and/or how they were generated by the purported
`
`in silico modeling of PK properties. For at least this reason, Patent Owner objects
`
`to the above documents as misleading, incomplete, and/or lacking relevance and
`
`because any probative value is substantially outweighed by the danger of unfair
`
`prejudice, confusing the issues, misleading the fact finder, undue delay, wasting
`
`time, and/or needlessly presenting cumulative evidence (FRE 106, 401, 402, and
`
`403). Further, Patent Owner objects to these documents under 37 C.F.R. § 42.65.
`
`To the extent these documents are, or contain, technical test or data from such a
`
`test, they lack support and explanation in a sufficient affidavit (37 C.F.R. § 42.65).
`
`Further, Patent Owner objects to these documents as not properly
`
`
`
`– 10 –
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`
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`authenticated under FRE 901 because Petitioner has not presented sufficient
`
`evidence that the documents are authentic or that the documents are self-
`
`authenticating under FRE 902. Patent Owner further objects on the basis that these
`
`are not original documents under FRE 1002, authentic duplicates under FRE 1003,
`
`nor documents that falls under any exceptions to the original-document
`
`requirement, including those of FRE 1004.
`
`To the extent exhibits 1052, 1053, 1054, 1055, 1056, 1057, 1058, and 1059
`
`are being offered to prove the truth of the matter asserted, Patent Owner also
`
`objects to the exhibits as constituting inadmissible hearsay under FRE 801 and 802
`
`that does not fall under any exceptions, including those of FRE 803, 804, 805, or
`
`807.
`
`Patent Owner further objects to any paragraph of exhibits 1002 and 1003 to
`
`the extent they rely on exhibits 1052, 1053, 1054, 1055, 1056, 1057, 1058, and
`
`1059 for at least the reasons identified here.
`
`Exhibits 1004, 1005, 1007, 1008, 1009, 1010, 1011, 1014, 1015, 1016,
`
`1017, 1018, 1019, 1021, 1022, 1023, 1024, 1025, 1026, 1028, 1031, 1033, 1035,
`
`1036, 1037, 1038, 1039, 1040, 1042, 1043, 1044, 1045, 1046, 1047, and 1051
`
`To the extent exhibits 1004, 1005, 1007, 1008, 1009, 1010, 1011, 1014,
`
`1015, 1016, 1017, 1018, 1019, 1021, 1022, 1023, 1024, 1025, 1026, 1028, 1031,
`
`1033, 1035, 1036, 1037, 1038, 1039, 1040, 1042, 1043, 1044, 1045, 1046, 1047,
`
`
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`– 11 –
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`IPR2023-00512
`Patent Owner’s Objections to Evidence
`and 1051 are being offered to prove the truth of the matter asserted, Patent Owner
`
`objects to the exhibits as constituting inadmissible hearsay under FRE 801 and 802
`
`that does not fall under any exceptions, including those of FRE 803, 804, 805, or
`
`807.
`
`Patent Owner further objects to any paragraph of exhibits 1002 and 1003 to
`
`the extent they rely on exhibits 1004, 1005, 1007, 1008, 1009, 1010, 1011, 1014,
`
`1015, 1016, 1017, 1018, 1019, 1021, 1022, 1023, 1024, 1025, 1026, 1028, 1031,
`
`1033, 1035, 1036, 1037, 1038, 1039, 1040, 1042, 1043, 1044, 1045, 1046, 1047,
`
`and 1051 for at least the reasons identified here.
`
`
`
`
`
`
`
`
`
`
`
`
`Respectfully submitted,
`
`
`By: /Heather M. Petruzzi/
`Heather M. Petruzzi (Reg. No. 71,270)
`Laura Macro (Reg. No. 80,908)
`Gabriel J. Rosanio (Reg. No. 81,426)
`
`Counsel for Celgene Corporation
`
`– 12 –
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`
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`IPR2023-00512
`
`CERTIFICATE OF SERVICE
`I hereby certify that, on August 3, 2023, I caused a true and correct copy of
`
`the following materials:
`
` Patent Owner’s Objections to Evidence Under 37 C.F.R. § 42.64
`
`to be served via email on the attorneys identified in the Petition for Petitioner
`
`Apotex, Inc. (Paper No. 1), who consented to electronic service:
`
`Vishal C. Gupta (Reg. No. 67,284)
`John J. Molenda (Reg. No. 47,804)
`Tyler Doh (Reg. No. 80,274)
`Steptoe & Johnson LLP
`1114 Avenue of the Americas
`New York, NY 10036
`Tel: (212) 506-3900
`Fax: (212)-506-3950
`
`Robert Kappers (Reg. No. 70,202)
`Steptoe & Johnson LLP
`227 West Monroe Street
`Suite 4700
`Chicago, IL 60606
`Tel: (312)-577-1300
`
`Azacitidine@Steptoe.com
`
`/Gabriel J. Rosanio/
`Gabriel J. Rosanio (Reg. No. 81,426)
`Wilmer Cutler Pickering Hale and Dorr
`LLP
`7 World Trade Center
`250 Greenwich Street
`New York, NY 10007
`Tel: 212-295-6363
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Petitioner’s Appendix of Exhibits
`
`Exhibit No. Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`U.S. Patent No. 8,846,628 (the “’628 patent”)
`
`Declaration of Dr. Graham Buckton (“Buckton Decl.”)
`
`Declaration of Dr. Hannah K. Batchelor (“Batchelor Decl.”)
`
`WO 2004/082619 (“Ionescu”)
`
`WO 2004/103358 (“Atadja”)
`
`Gibson, M., Ch. 11, Oral Solid Dosage Forms, PHARMA.
`PREFORMULATION AND FORMULATION, CRC Press (2001)
`(“Gibson”)
`
`Vidaza Label 2004
`
`Vidaza Label 2007
`
`WO 2004/082822 (“Ionescu ʼ822”)
`
`Press Release, Pharmion, “Clinical Data Presented on Pilot
`Pharmacokinetic Study of Oral Azacitidine” (June 2, 2007)
`(““Pharmion-PR”)
`
`Press Release, Pharmion, “Pharmion’s Oral Azacitidine Granted
`Fast Track Status for Myelodysplastic Syndromes” (August 29,
`2007) (“Pharmion-PR II”)
`
`Pharmion Corporation, Form 10-K (February 29, 2008) (“Pharmion
`10-K”)
`
`Excerpts from Rowe, R.C., et al., Handbook of Pharma. Excipients,
`Pharma. Press, 5th ed. (2006) (“Handbook”)
`
`– i –
`
`
`
`
`
`
`
`
`Exhibit No. Description
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`Chan et al., “5-Azacytidine Hydrolysis Kinetics Measured by High-
`Pressure Liquid Chromatography and 13C-NMR Spectroscopy,”68
`(7) J Pharma. Scis. 807 (1979) (“Chan”)
`
`Kelley et al., “Furanose-Pyranose Isomerization of Reduced
`Pyrimidine and Cyclic Urea Ribosides,” 29 J. Med. Chem. 2351
`(1986) (“Kelley”)
`
`U.S. Patent No. 3,817,980 (“Vorbruggen”)
`
`Marcucci, G., et al., “Bioavailability of Azacitidine Subcutaneous
`Versus Intravenous in Patients With the Myelodysplastic
`Syndromes,” 45 J. Clin. Pharmacology 597 (2005) (“Marcucci”)
`
`Thomson, A., “Back to basics: pharmacokinetics,” 272 Pharma. J
`769 (2004) (“Thomson”)
`
`U.S. Patent Publication No. 2006/0074046 (“Redkar”)
`
`Dintaman, et al., Pharmaceutical Research, 1999, 16(10), 1550-
`1556 (“Dintaman”)
`
`U.S. Patent Publication No. 2004/0162263 (“Sands”)
`
`Application File History for the ʼ628 Patent, U.S. App. No.
`12/466,213 (“File History”)
`
`U.S. Patent No. 3,350,388
`
`Piskala, A. and Sorm, F., Collect. Czech. Chem. Commun., 29,
`2060-2076 (1964)
`
`Piskala, A. and Sorm, F., GB 1227691 (1971)
`
`U.S. Publication No. 2008/0057086 (“ʼ086 Publication”) (filed as
`U.S. Application No. 11/849,958 (“ʼ958 application”))
`
`– ii –
`
`
`
`
`
`
`
`
`Exhibit No. Description
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`GastroPlus version 5.2 Manual (“GP5.2 manual”)
`
`Exhibit number not used
`Kotke, M.K. and Rudnic, E.M, Ch. 10, Tablet Dosage Forms,
`MODERN PHARMACEUTICS, 4th ed. (2002) (“Modern
`Pharmaceutics”)
`Ch. 45, Oral Solid Dosage Forms, and Ch. 46, Coating of
`Pharmaceutical Dosage Forms, REMINGTON, THE SCIENCE
`AND PRACTICE OF PHARMACY, 20th ed., Lippincott Williams
`& Wilkins (2000) (“Remington”)
`
`Dover, G.J., et al., 5-Azacytidine Increases HbF Production and
`Reduces Anemia in Sickle Cell Disease: Dose-Response Analysis
`of Subcutaneous and Oral Dosage Regimens, Blood, 66(3): 527-532
`(Sep. 1985) (“Dover”)
`
`Hardy et al., Drug Delivery to the Gastrointestinal Tract, 1989 Ch.
`7, 83-96 (“Hardy”)
`
`Ewe et al., Digestive Diseases and Science, 1991, 36(2) 146-152
`(“Ewe”)
`
`Stoltz et al., Development of an Oral Dosage Form of Azacitidine:
`Overcoming Challenges in Chemistry, Formulation, and
`Bioavailability, Blood 108:4850 (2006) (“Stoltz”)
`
`Exhibit number not used
`
`U.S. Provisional Application No. 61/053,609 (“ʼ609 provisional”)
`
`Schwarz et al., Gastrointestinal Transit Times in Mice and Humans
`Measured With 27Al and 19F Nuclear Magnetic Resonance,
`Magnetic Resonance in Medicine 48:255-261, 260 (2002)
`(“Schwarz”)
`
`– iii –
`
`
`
`
`
`
`
`
`Exhibit No. Description
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`Amidon et al., A theoretical basis for a Biopharmaceutic Drug
`Classification - The correlation of in vitro drug product dissolution
`and in vivo bioavailability. Pharm. Res., 12:413-420 (1995)
`(“Amidon”)
`
`Buck et al., Prediction of Human Pharmacokinetics Using
`Physiologically Based Modeling: A Retrospective Analysis of 26
`Clinically Tested Drugs, Drug Metabolism & Disposition,
`35(10):1766-1780 (2007) (“Buck”)
`
`Dannenfelser et al., Development of Clinical Dosage Forms for a
`Poorly Water Soluble Drug I: Application of Polyethylene Glycol–
`Polysorbate 80 Solid Dispersion Carrier System, J Pharma. Sci.,
`93(5):1165-1175 (2004) (“Dannenfelser”)
`
`Press Release, Simulations Plus, Inc., “Simulations Plus Releases
`GastroPlus(™) 5.2” (Nov. 30, 2006) (“GP5.2 PR”)
`
`IARC Monographs on the Evaluation of Carcinogenic Risks to
`Humans, Pharmaceutical Drugs, Vol. 50, 1990 (“IARC”)
`
`Israili et al., The Disposition and Pharmacokinetics in Humans of 5-
`Azacytidine Administered Intravenously as a Bolus or by
`Continuous Infusion, Cancer Res. 36:1453-1461 (1976) (“Israili”)
`
`Kuentz et al., A strategy for preclinical formulation development
`using GastroPlusTM as pharmacokinetic simulation tool and a
`statistical screening design applied to a dog study, Euro. J. Pharma.
`Sci., 27:91-99 (2006) (“Kuentz”)
`
`Li et al., IV-IVC Considerations in the Development of Immediate-
`Release Oral Dosage Form, J Pharma. Sci. 94(7):1396-1417 (2005)
`(“Li”)
`
`Obach et al., The Prediction of Human Pharmacokinetic Parameters
`from Preclinical and In Vitro Metabolism Data, J. Pharma. & Exp.
`Thera., 283(1):46-58 (1997) (“Obach”)
`
`– iv –
`
`
`
`
`
`
`
`
`Exhibit No. Description
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`Parrott & Lavé, Prediction of intestinal absorption: comparative
`assessment of gastroplus™ and idea™, Euro. J. Pharma. Sci.,
`17:51-61 (2002) (“Parrott”)
`
`Simulations Plus, Inc., Form 10-QSB (January 16, 2007) (“SLP 10-
`QSB”)
`
`FDA Guidance for Industry, Guideline for the Format and Content
`of the Human Pharmacokinetics and Bioavailability Section of an
`Application, February 1987 (“PK Guideline”)
`
`U.S. Provisional Application No. 61/157,875 (“ʼ875 provisional”)
`
`U.S. Provisional Application No. 61/201,145 (“ʼ145 provisional”)
`
`The SDF file for the PubChem compound entry for Azacitidine
`(PubChem CID 9444) (September 16, 2004)
`(“Conformer3D_CID_9444 (1).sdf”), printed to PDF
`
`ADMET Predictor Output file (“Azacitidine ADMET.txt”), printed
`to PDF
`
`CDD file for 200 mg dose (“Azacitidine 200 mg.cdd”), printed to
`
`IV plasma concentration-time data file for 200 mg dose
`(“Azacitidine 200 mg.ipd”), printed to PDF
`
`Result data file for 200 mg dose (“Azacitidine 200 mg All
`Data.txt”), printed to PDF
`
`CDD file for 400 mg dose (“Azacitidine 400 mg.cdd”), printed to
`
`IV plasma concentration-time data file for 400 mg dose
`(“Azacitidine 400 mg.ipd”), printed to PDF
`
`– v –
`
`
`
`Exhibit No. Description
`
`1059
`
`Result data file for 400 mg dose (“Azacitidine 400 mg All
`Data.txt”), printed to PDF
`
`– vi –
`
`
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